Guanidine and guanidinium salt catalyzed enantioselective phosphorus carbon bond formation reactions 1

Chapter Chapter Asymmetric Phosphorus-Carbon Bond Formation Reactions Chapter Phosphorus is an essential element for synthetic chemistry and life science. After the Wittig reaction was discovered in 1954, the organic chemistry of phosphorus became a highly active field.1 Phosphorus is not only critical for many reagents, but also probably the most prominent ligands, in terms of structural and electronic diversity in metal-catalyzed reactions2 and nucleophilic phosphine organocatalysis.3 Molecules containing a phosphonic [P(O)(OH)2], a phosphinic [P(O)(OH)R] or a phosphonate [P(O)(OR)2] group and an amino group can be regarded as analogues of amino acids. α-Amino phosphonic acids and their phosphonate esters are excellent inhibitors of protease and antibodies.4 The synthetic and biological abilities of phosphorus compounds depend on their enantiopurities. Therefore, synthesis of enantiomerically pure organophosphorus compounds has received considerable attention. Such compounds are typically prepared by resolution of the racemic phosphorus compounds5, which limits the scope of the enantiopure organophosphorus compounds. The direct approach to build phosphorus-carbon (P-C) bonds, which was a convenient method to generate structurally diversified organophosphorus compounds, provided many model reactions to develop the asymmetric P-C bonds formation reactions. There are several general methods to generate P-C bonds: (a) addition to unactivated olefins promoted by radical initiators or transition metals. (b) the phospha-Michael reaction of electron-deficient alkenes, most commonly promoted in the presence of a basic catalyst (e.g. K2CO3,8 alkaline alkoxides in alcoholic solution9) or by using a strong base10 (e.g. NaH, nBuLi, Et2Zn) in stoichiometric amount, the use of tetramethylguanidine (TMG), 11 Lewis acid 12 or under microwave conditions; 13 Among various methods to generate P-C bonds, the direct addition of P(O)-H bonds (dialkyl phosphonate [(RO)2P(O)H] or dialkyl phosphine oxides [R2R(O)H]) across Chapter alkenes is one of the most convenient and atom economical routes. 14 1.1 Asymmetric phospha-Michael reactions 1.1.1 Asymmetric phospha-Michael reactions through chiral starting materials and chiral auxiliaries Asymmetric versions of phospha-Michael reactions mainly deal with substratecontrolled diastereoselective additions. Yamamoto and co-workers 15 developed the first substrate-controlled diastereoselective addition of phosphorus nucleophiles to unsaturated nitroalkenes derived from sugar. Albeit only with moderate stereoselectivities under the reaction conditions (heated to 70 oC for 12 h), this work demonstrated a possible way for the preparation of sugar analogues with a phosphorus atom in place of oxygen in the hemiacetal ring (Scheme 1.1). MeO O O O O2 N Me Me MeO O P Me H OMe O O O o benzene, 70 C O2 N Me P Me Me O OMe HO HO HO O P Me HO OR OH HO O P Me HO OR + OH Scheme 1.1. Yamamoto’s substrate-controlled diastereoselective addition of P nucleophiles to unsaturated nitrosaccharides. Yamashita and co-workers16 described the diastereoselective addition of various phosphorus nucleophiles to Z-configured nitroalkene acceptors bearing the sugar residue in the presence of Et3N at 90 oC (Scheme 1.2). The major product was L-Idose derivatives due to the steric hindrance caused by 3-O-alkyl group of the sugar, as well as R2 and R3 group of the phosphorous compounds. The ratio of L-Idose and D-gluco Chapter derivatives increased from 2:1 to 11:1 with different steric size of R1-R3 (11:1 was obtained when R1 = Me, R2 = R3 = Ph, X = O). However, when primary phosphine (R1 = Bn, R2 = mesityl, R3 = H, X = lone pair) was employed, no reaction was observed. X R2 P R3 NO2 R 1O O + O R2 O Me R 1O X P H R3 O o Et3N, 90 C O Me NO2 O Me Me (2:1 - 11:1 dr) D-gluco NO2 R 1O R = Me, Ac, Bn; R = OMe, OEt, Ph, OBn, Mes; R = H, OMe, OEt, Ph, OBn; X: O or lone pair electrons O L-ido O O Me Me Scheme 1.2. Yamashita’s diastereoselective addition of various phosphorus nucleophiles to Z-configured nitroalkene acceptors 5. 7a-f Condition A: O Et3 N (0.3 eq.), r.t. MeO P + (MeO) 2P(O)H Condition B: MeO 100 oC R (R)- 8a-f AcO O NO R R: O Me O O O Me Me a O Me b BnO O Me Me O AcO O BnO O MeO NO2 + Condition A 8a: 81% (89:11 R/S) 8b: 94% (66:34 R/S) O O 8c: 57% (67:33 R/S) Me Me 8d: 81% (87:13 R/S) 8e: 8% (66:34 R/S) c 8f: 0% O P NO2 MeO R (S) -8a-f Condition B 83% (35:65 R/S) 91% (48:52 R/S) 55% (38:62 R/S) 65% (22:78 R/S) 0% 0% O O O OMe d Me e O O Me Me O Me f Scheme 1.3. Yamamoto’s stereoselective addition of dimethyl phosphonate to the Econfigured nitro olefins. Chapter Yamamoto and co-workers17 carried out a systematic study on the stereoselective addition of dimethyl phosphonate to the E-configured nitroalkenes 7a–f (Scheme 1.3). Two different conditions were employed and it was found that the stereochemical outcome were opposite. Condition A (0.3 eq of Et3N) gave predominantly the R stereoisomer, whereas the S stereoisomer was obtained as a major component in the case of condition B (heated to 100 oC in the absence of base). In most cases (except e, f), the yields obtained were moderate to good (55 to 94%). Me Me Ph Ph OH O a,b O 98% OH Me Me Ph Ph Ph Ph O O O P O O H Ph Ph R 10 HO NO2 O P HO NO2 R 11 ee = 81-95% 86-91 % c Me Me 65-94 % Ph Ph O O O P O O Ph Ph R d, e NO 12, de = 84-96% R = Ph, pBiph, 3,4,5-(MeO)3Ph, pMePh, 2-Naphthyl Scheme 1.4. Enders’s asymmetric phospha-Michael reaction to nitroalkenes. Reagents and conditions: (a) 1.3 eq. PCl3/Et3N, THF, oC; (b) H2O/Et3N, THF, oC) (R,R)-9, TMEDA, Et2Zn, -78 oC; (d) TMSCl, NaI, CH3CN, reflux; (e) DCM/H2O, r.t. Enders and co-workers 18 reported an asymmetric phospha-Michael reaction to nitroalkenes in the presence of Et2Zn and N,N,N’,N’-tetramethylenediamine (TMEDA). The phosphorus nucleophile 10 was easily synthesized from TADDOL (9) and PCl3 in excellent yield (Scheme 1.4). The C2-symmetry of the ligand avoided the formation of a new stereogenic center at phosphorus. TMEDA played an essential Chapter role to greatly improve the solubility of the organozinc-phosphorus compounds, which was reactive but insoluble. The addition of TMEDA made the reaction possible even at -78 oC with higher de values. This reaction was proven to be high yielding (86–91 %) and a high stereoselectivity (84–96 % de) was also achieved. Moreover, diastereomerically pure products could be obtained easily by recystallization or preparative HPLC. The adducts could finally be converted into the phosphonic acid without racemization. The same group19 used the phosphonate 10 to carry out the asymmetric addition of acceptor 13 under heterogeneous conditions, Fe2O3 mediated KOH (Scheme 1.5). No reaction was observed when only KOH was used in the absence of metal oxide, which indicated that the presence of the solid support was essential for the activation of the P-H bond towards deprotonation. The phosphonates 16 were obtained in moderate to good yields and with very good diastereoselectivities. The auxiliary was easily cleaved without detectable epimerization or racemization to give compound 15, by refluxing the addition products in MeCN in the presence of TMSCl/NaI and subsequently hydrolyzing the resulting silyl ester. Due to their high polarity, 15 were first converted into their respective methyl esters in order to facilitate their purification. Although alkyl-substituted malonates showed even higher reactivity leading to improved yields (85–87%), unsatisfactory ee values were obtained (15–30 %). Haynes, Yeung and co-workers 20 reported the conjugate addition reaction of configurationally stable lithiated P-chiral tert-butyl(phenyl)phosphine oxide 17 with α,β-unsaturated carbonyl compounds (Scheme 1.6). Whereas aldehydes exclusively underwent 1,2-addition, the cyclic enones 18 and 19 and the unsaturated esters 22a–c yielded the 1,4-addition products 20, 21 and 23a–c, respectively, with moderate to Chapter excellent diastereoselectivities. It should be noted that this reaction proceeded with retention of configuration at the phosphorus center. Me Me Ph Ph O O O P O O H Ph Ph 10 a 64-75 % Me Me R MeO O CO2 Me P CO 2Me MeO R 16, (84-94% ee) CO 2Me CO2Me 13 72- 86 % (2 steps) Ph Ph O O CO2 Me O P CO 2Me O O Ph Ph R b,c HO d O CO2 H P CO 2H HO R 14 , (82-94% de) 15 MeO O R= O MeO Me OMe Scheme 1.5. Enders’s asymmetric phospha-Michael reaction under heterogeneous conditions. Reagents and conditions: (a) Fe2O3/KOH, DCM, rt; (b) TMSCl, NaI, MeCN, reflux; (c) DCM/H2O; (d) CH2N2, MeOH/H2O. Helmchen and co-worker21 utilized Ph2PLi for the addition to (–)-(1R)-tert-butyl myrtenate (24) (Scheme 1.7). The reaction proceeded smoothly and diastereoselectively to give 25, which was further transformed to the phosphine ligand 27 in steps. This ligand was then employed in palladium-catalyzed asymmetric allylic alkylation reactions with the cyclic substrates 28. Good yields of the substitution products along with good to excellent enantioselectivities were easily achieved in the case of six- and seven-membered rings. Chapter O O 1. LDA or nBuLi Ph P Ph P t t H 2. Bu Bu O 17 18: n = 20 or 21 n 19: n = O O Ph P O Ph P t O Bu t Bu 21 81%, 96% de O Ph P 1. LDA or nBuLi t Bu 2. R R OMe O n 20 78%, 96% de O Ph P t H Bu 17 O Ph OMe P t Bu O Ph O H Scheme 1.6. Haynes’s conjugate butyl(phenyl)phosphine oxides. OMe Me 23b: 78%, 82% de 23a : 63% O 23 O 22a : R = H 22b: R = Ph 22c : R = Me O Ph P OMe t Bu O Ph P t Bu OMe addition O 23c : 67%, 54% de reaction of P-chiral tert- PPh a CO2 tBu 25 CO2 tBu 24 b PPh 2BH PPh c CO2 H 27 CO2H 26, overall 54% yield CO2R X MCH(CO 2R)2 CO2 R PdL * L = 27 n n 29 28 n = 1-3; X = Cl, OAc; R = Me, tBu; M = Li, Na yield: 73-93%; 70 - >99% ee Scheme 1.7. Helmchen’s stereoselective addition of lithiated phosphines. Reagents and conditions: (a) Ph2PH/BuLi (1.8 euqiv.), THF, -78 oC, 3h, then Na2SO4 . 10H2O; (b) i BH3.THF, -50 oC; ii CF3CO2H, then NaOH, 90%; iii NaH, THF, 25 oC, BH3.THF, -78 oC, 1N HCl; (c) DABCO, 1.1 eq., 100 oC, 1h. Feringa and co-workers 22 presented the Michael reaction of lithio8 Chapter diphenylphosphine to γ-butenolides (Scheme 1.8). The reaction with methoxy-2(5H)furanone (30a) furnished the lactone (31) in high yield and with high diastereoselectivity in favor of trans-isomer. Moreover, using the enantiomerically pure butenolide synthon (5R)-menthyloxy-2(5H)-furanone 30b, the asymmetric Michael addition of lithio-diphenylphosphide followed by trapping the intermediate with chlorodiphenylphosphine to afford lactone 32 as a single diastereoisomer. The enantiomerically pure (S,S)-CHIRAPHOS 33 was obtained from 32 in an overall yield of 35%. O O Ph2PLi; H 3O O 74 % OMe 30a + O Ph2P OMe 31 O O 1. LiPPh2 O O 2. Ph2PCl OR 30b: R = Ph2 P iPr Ph2 P 1. LiAlH4 ; 2. TsCl/Py; 3. LiAlH Ph2 P PPh2 35% overall yield OR 32 33 Me Scheme 1.8. Feringa’s Michael reaction of lithio-diphenylphosphine to γ-butenolides. Phosphine-boranes can react as nucleophiles like their analogs of the corresponding secondary phosphines which are unstable in air. Such phosphorus nucleophiles are usually uncommon, since their synthetic method (prepared by complexation of phosphines and boranes) involved handling of highly corrosive and air-sensitive phosphines. Corre and co-workers23 used an in-situ protocol for the synthesis of phosphineboranes 34 from diphenylphosphine oxides (Scheme 1.9). The borane moiety can be regarded as a protecting group, because it prevents oxidation of the phosphorus atom and its cleavage can be easily achieved in the presence of an excess of a highly Chapter nucleophilic amine. 34 was shown to be applicable in NaH-catalyzed Michael reactions to the biselectrophile 35. Although 35 was reacted as a mixture of E/Z isomers, a single diastereomer 36c was obtained from the reaction of Ph2P(BH3)Na and 35 in THF. On the other hand, the utilization of a stoichiometric amount of KOH yielded both diastereoisomers 36a and 36b, which could be separated by crystallization. BH3 O Ph P H Ph MeO2C LiAlH 4, NaBH , CeCl3 65 % O O MeO2C Me Me 34, NaH, THF -30 to oC Ph P H Ph 34 BH PPh MeO2C O 50 % O MeO2C Me Me PPh E/Z-35 BH 36c 34, KOH MeOH, oC BH BH PPh MeO2C PPh O O MeO2C PPh BH 36a (46%) MeO2C Me Me O + O MeO2C Me Me PPh BH 36b (14%) Scheme 1.9. Corre’s stereoselective addition of Phosphine-borane complex to biselectrophile 37. Quirion and co-workers24 described a diastereoselective synthetic route to obtain chiral amidophosphonates. The nucleophilic attack of lithiated 34 occured from the Si face to give the tertiary phosphine-boranes 38 in moderate yields and diastereomeric excesses (Scheme 1.10). 10 Chapter treated with TMSCl and transformed into the corresponding bis(trimethylsilyl) phosphinites 40a–c. These compounds were then reacted with the enantiopure acrylimides 41a, b yielding the addition products 42a–f. These enol ethers were assumed to adopt the Z configuration as depicted 43. A diastereoselective protonation process employing EtOH finally yielded the desired products phosphinic acids 42a–f in very good yields. The diphenylmethyl-substituted oxazolidinone 41b gave much better diastereoselectivities than its benzyl analogue 41a. The auxiliary could be cleaved successfully using LiOH (Scheme 1.11). 1.1.2 Metal-catalyzed asymmetric phospha-Michael reactions. The phospha-Michael addition of secondary phosphines was conducted via organonickel complex catalyst.26 A range of phosphines 44 were tested. Higher steric hindrance led to a better result (46e, 95% yield, 94% ee), albeit longer reaction time was required (Scheme 1.12). (R)-(S)-Pigiphos = Fe P Fe PPh2 Ph2 P 45 [(Pigiphos)Ni(THF)](X)2 R 2PH + 44a-e Cy CN 46a-e i Ph P Pr P Pr CN 46a : 8h 71%yield 70% ee 46b : 24h 10%yield 32% ee 46c: 24h 70% ee Cy P R2 P CN t t Bu CN Ph Bu P CN i Ad CN Ad P CN 46d : 8h 87%yield 89% ee 46e :96h, 95%yield 94% ee Scheme 1.12. Organonickel complex catalyzed enantioselective phospha-Michael addition of secondary phosphines. 1.1.3 Organocatalyst catalyzed asymmetric phospha-Michael reactions. Recently, Melchiorre and co-workers 27 reported an organocatalytic asymmetric 12 Chapter hydrophosphination of nitroalkenes. A bifunctional Cinchona alkaloid catalyst 47 provided a new organocatalytic strategy for the enantioselective addition of diphenylphosphine to a wide range of nitroalkenes, yielding optically active βnitrophosphines. Considering the instability of phosphine adducts, a sequential onepot formation of the air-stable phosphine-borane complex derivative 49a-e facilitated the purification process (Scheme 1.13). Due to the background reactions, only moderate enantioselectivities (highest 67% ee) were observed. The synthetic potential of this method was evaluated, affording the enantiopure aminophosphine 50 (ee of 49a was improved to 99% through a single crystallization), which could be a potentially useful class of P, N-ligands. (Ph)2 PH + HCOOH NaBH NO2 Ph Catalyst 47 PPh o Et2O-IPA 9:1, -40 C Ph THF/-40 oC Ph 30 Ph BH P NO2 1. NiCl2. 6H 2O NaBH4 , MeOH -10 oC to r.t. 2. Boc 2O, r.t. 49a 36% yield, 99% ee (crystallization) Cinchona alkaloid catalyst = F3C CF3 NO2 Ph 48a 86% yield, 67% ee Ph Ph BH P NHBoc Ph 50 95% yield, 99% ee Ph Ph BH P NO2 Me HN N HN MeO 47 N Ph BH P NO2 F 49b 67% yield, 52% ee S Ph Ph Ph BH P NO2 S 49d 71% yield, 36% ee 49c 83 % yield, 45% ee 24% yield, 99% ee after crystallization Ph Ph BH P NO2 OBn 49e 90% yield, 60% ee 37% yield, 99% ee af ter crystallization Scheme 1.13. Melchiorre’s organocatalytic asymmetric hydrophosphination of nitroalkenes. Melchiorre28 and Cordova29 published an asymmetric hydrophosphination of α,β13 Chapter unsaturated aldehydes by the protected diarylprolinol on the same issue of Angew. Chem. Int. Ed. independently. The former group employed the chiral pyrrolinol derivative salts 50 as catalyst, affording the 1,4-addition products exclusively along with up to 94% ee. Furthermore, an enantioenriched aminophosphine 54 was synthesized to demonstrate the synthetic utility (Scheme 1.14A). Comparable results were achieved by the latter group. In this case, the same catalyst 50 with different anion was utilized. A β-phosphine oxide acid 55 was obtained from 52 through oxidation by NaClO2 (Scheme 1.14B). 50 N H OTMS Ar Ar Ar = 3,5-(CF3 )2C 6H O R + Ph 2H 1. BnNH2/NaBH toluene 2. CH 3CO2H, NaBH4 Ph 52a-d A 50 .2-f luorobenzoic o CHCl3, C NaClO2 52e N Ph H 54 71% yield, 87% ee CH CO 2H NaBH PPh2 acid R O 52a, e 51a: R = Ph 51e: R = 4-ClC6 H4 B Ph BH P O 52a R + Ph2 H Ph THF, -40 oC R OH 30 53a: 72% yield, 94% ee 53b: 60% yield, 84% ee 53c: 64% yield, 90% ee 53d: 62% yield, 81% ee Ph Ph BH P R Et2O 51a: R = Ph 51b: R = Me 51c: R = 2-furyl 51d: R = oCl-C 6H O CH CO 2H NaBH PPh2 50 .p-NO2C 6H 4CO2H Ph Ph P O Ph Ph BH P MeOH, oC R OH 53a: 85% yield, 83% ee 53e: 79% yield,92% ee COOH R 55 65% yield, 92% ee Scheme 1.14. Proline derivatives catalyzed hydrophosphination of α,β-unsaturated aldehydes. Wang and co-workers 30 developed the enantioselective conjugate addition of diphenyl phosphonate to various nitroolefins catalyzed by quinine (56). The substrates 14 Chapter included acceptors derived from aromatic, hetero-aromatic and aliphatic aldehydes. To increase the level of ee, the reaction temperature was decreased to -50 oC, and moderate to good results were observed (45 – 88% ee). However, fairly long reaction time (6 days) was required (Scheme 1.15). H N HO 56 = H MeO N Quinine OPh PhO P O + R H NO2 10 mol% catalyst 56 xylene, -55 o C OPh PhO P O NO R 57 OPh PhO P O OPh PhO P O OPh PhO P O NO2 NO2 F NO2 MeO 57a: 82% yield, 70% ee 57b: 85% yield, 77% ee 57c: 78% yield, 75% ee OPh PhO P O S OPh PhO P O NO2 57d: 79% yield, 88% ee OPh PhO P O NO2 57e: 77% yield, 45% ee NO2 57f: 62% yield, 60% ee Scheme 1.15. Quinine catalyzed enantioselective conjugate addition of diphenyl phosphonate to nitroolefins. Terada and co-workers 31 demonstrated the highly enantioselective 1,4-addition reaction of nitroalkenes with diphenyl phosphonate catalyzed by an axially chiral guanidine 58. In order to obtain good results (85 – 97% ee), the reactions were conducted under low reaction temperature (-40 oC). More importantly, the low catalyst loading (1 to mmol %) did not affect the reaction rate (0.5 to 7h) and chemical yields (84 to 98%). A broad range of nitroalkenes, bearing not only aromatic but also aliphatic substituents, was applied to obtain enantioenriched products. β15 Chapter amino phosphonate derivative 59 of biological and pharmaceutical importance was synthesized without loss of the enantiopurity (Scheme 1.16). Ar H N G N N H Ar OPh PhO P O H + NO2 R OPh PhO P O 58: G = Ph2CH-, Ar = 3,5-tBu2C 6H 3OPh PhO P O (R)-58 (1 mol%) t er t-butyl methyl ether -40 oC, 0.5 to h OPh PhO P O NO2 NO2 R 57 OPh PhO P O NO2 MeO 57a: 94% yield, 92% ee 57c: 91% yield, 91% ee OPh PhO P O NO2 Br 57g: 97% yield, 91% ee OPh PhO P O OPh PhO P O NO2 O NO2 NO2 NO2 57h: 96% yield, 97% ee 57i: 79% yield, 89% ee 57a NiCl2, NaBH 4, Boc 2O MeOH/CF3 CH2OH = 10/1 r.t., 3.5 h 77% yield 57f: 87% yield, 85% ee OPh PhO P O NHBoc Ph 59 Scheme 1.16. Terada’s guanidinine catalyzed 1,4-addition reaction of nitroalkenes with diphenyl phosphonate. 1.2 Asymmetric hydrophosphonylation of imines The hydrophosphonylation of imines afforded a method for construction of P-C bonds,32 which is usually promoted by metal complex33 or base34. 1.2.1. Chiral starting materials and chiral auxiliaries assisted asymmetric hydrophosphonylation of imines. Smith and co-workers 35 reported the synthesis of a series of α-amino phosphonates with high optical purities. Lithium diethyl phosphonate (LiPO3Et2) was 16 Chapter found to afford a fast reaction with chiral imines derived from corresponding enantiopure amine and aldehydes (Scheme 1.17). Moderate to good yields (36 – 81%) and high diastereoselectivites (95 – 98% de) were observed when imine 60 derived from aliphatic aldehydes were employed. However, the phenyl aldimine 61e only yielded 76% de adducts. The chiral directing groups were removed and α-amino phosphonates 62a-e were obtained without great loss of enantiomeric purity. A transition state was proposed that the chelation of the lithium cation by the ether oxygen and imine nitrogen created a rigid, five-membered ring. The phosphite anion attacked from the Re face to generate R,R diastereomers. CH2 OMe CH2 OMe N Ph LiPO3 Et2 THF R 60 HN R Ph P(OEt) O NH H2 Pd(OH) selected examples: 61a R = Cy 68% yield 95% de 61b R = CyCH 70% yield 98% de 61c R = i Bu 81% yield 98% de 61d R = BnOCH2 36% yield 96% de 61e R = Ph yield 90% 76% de PO3Et2 H Me Li O r e f ace N R H R P(OEt) O 62a 96% ee 62b >99% ee 62c >99% ee 62d >98% ee 62e 71% ee 63 Scheme 1.17. Smith’s synthesis of a series of α-amino phosphonates with high optical purities. Evans and co-workers 36 designed a synthetic approach to α-amino phosphonic acids involving the addition of metallo phosphites to enantiomerical enriched sulfinimines derived from sulfinate (Scheme 1.18). Two sulfinimines were tested (64a Ar = Ph, 64b Ar = p-MeOPh) and up to 93% and 97% ee were obtained, respectively. The major diastereisomer was purified after the desulfinylaion reaction was carried out by using CF3CO2H and no epimerization of carbon chiral center was observed. 17 Chapter H O p-Tol S N O (RO)2P (RO)2POM Ar THF, -78 oC H N S O (RO)2 P CF3 CO2H p-Tol Ar O 64 Ar 65a R = Et, Ar = Ph 65b R = iPr, Ar = p-MeOPh O (RO)2 P NH O (RO)2 P 66 NH NH OMe 66a 93% ee 66b 97% ee Scheme 1.18. Evans’s synthetic approach to chiral α-amino phosphonic acids. 1.2.2 Metal-catalyzed hydrophosphonylation reaction of imines N R1 R2 O + MeO H P OMe H HN (R) - LPB 67 THF, - 15 o C, 24h R1 R = alkyl R2 OMe P OMe O 68 yield 27 - 87% ee 49 - 96% OMe (R) - LPB 67 = 68a 10 mol% (R) - LPB 67 70% yield, 96% ee K O O La O K NH O K R1 MeO O OMe P OMe O Ph O Ph NH R1 OMe 68b mol% (R) - LPB 67 82% yield, 92% ee P OMe O Scheme 1.19. Lanthanum-potassium-BINOL complex catalyzed hydrophosphination of imines. The first catalytic enantioselective example of hydrophosphonylation reaction of imines was achieved by Shibasaki and co-workers.37 Catalyst lanthanum-potassium- 18 Chapter BINOL complex (R)-LPB 67 was found to be more effective than lanthanum-lithiumBINOL complex. The best result 96% ee was given in 70% yield. A lower electron density for product nitrogen could improve the catalyst turnover. 68b was obtained with lower catalyst loading (5 mol%) and 92% ee was observed albeit 143 h was required (scheme 1.19). N t N R Ar N Al O Cl O Bu t t Bu Bu 69 (10 mol%) O + MeO H O Ar = HN P OMe H Ar OMe OMe P O Bu 70 HN THF, -15 oC, 24 h HN R Ar OMe OMe P O Br 70b >99% yield 95% ee 70a 90% yield 87% ee t HN O Ar OMe OMe P O 70 Ar OMe OMe P O 70c >94% yield 69% ee O HN OMe P OMe O O O OMe H P OMe A and B H THF, r.t. - h H2 N OMe P OMe O MeOH/H2 O, o C, h 70a 87% ee R1 NH anodic oxidation 69 (10 mol%) THF, - 15 oC, 24 h Ph Ph 71 72% yield HN R1 OMe R2 OMe P OMe O 72 NH2 A B OMe HN OMe Ph HN OMe P OMe O 72a 28% yield 88% ee Ph OMe P OMe O 72b 84% yield 94% ee Ph NH OMe P OMe O 72c 51% yield 15% ee 19 Chapter Scheme 1.20. Enantioselective hydrophosphonylation of various aldimines with Aluminum complex 69. Katsuki and co-workers 38 demonstrated that Aluminum complex 69 was an efficient catalyst for enantioselective hydrophosphonylation of various aldimines with dimethyl phosphonate (Scheme 1.20). High yields and high enantioselectivities were observed with the aromatic derived aldimines with N-protecting group 4-methoxy-3methylphenyl, which could be successfully deprotected to give the corresponding amine in a good yield without loss of enantiopurity. The reaction of aliphatic aldimines were conducted under condensation of aliphatic aldehydes and amines (A or B) followed by the subsequent hydrophosphonylation in one pot. Shibasaki and co-workers39 reported the first enantioselective catalytic approach to cyclic α-amino phosphonates by the hydrophosphonylation of cyclic imines in the presence of heterobimetallic lanthanoid complex 73 (Scheme 1.21). The pharmaceutically interesting (S)-4-thiazolidinylphosphonate 75 was obtained in excellent optical purities of up to 95% ee. K O O O Yb O K H3 C H 3C K O O O (R)-YbPB 73 (5 mol%) (MeO) P O N CH OMe P = potassium; B = (R)-(+)-binaphthol NH CH H3C + H P o CH THF/Toluene (1:7), 50 C, 48 h S OMe H 3C CH S 74 75 88% yield, 95% ee Scheme 1.21. Heterobimetallic hydrophosphonylation of cyclic imines. lanthanoid complex 73 catalyzed 20 Chapter 1.2.2 Organocatalytic hydrophosphonylation of imines Jacobsen and co-workers40 described a general and convenient access to a wide range of highly enantiomerically enriched α-amino phosphonates from Nbenzylimines 77 and di-(2-nitrobenzyl) phosphonate using chiral thiourea 76 (Scheme 1.22). The depronation of these products under mild conditions yielded the corresponding α-amino phosphonic acids 79 without any loss of enantiopurity. Me Me N O t-Bu S N H N H N HO O t-Bu O t-Bu O N Ph 76 (10 mol%) Ar Ar O P H + Et2 O O Ar H R Ar 78 77 52 Ar = o-NO2C6 H 81 selected examples Ar Ar O O P R H , Pd/C R O HO P O HO HN Ph NH 18 examples - 93% yield - 99% ee O Ph O P O HN Ph 78a 87% yield 98% ee Ar Ar 79a 87% yield 97% ee 79b 89% yield 96% ee O O P O HN Ph 78b 90% yield 96% ee Scheme 1.22. Jacobsen’s chiral thiourea catalyzed hydrophosphination of imines. Akiyama and co-workers 41 reported a chiral Brønsted acid, derived from (R)BINOL, which catalyzed reaction of the hydrophophonylation of imines with diisopropyl phosphonates leading to α-amino phosphonates in good to high enantioselectivity. Aldimines 81f derived from cinnamaldehyde derivatives exhibited high enantioselectivity (Scheme 1.23). The authors proposed a reaction mechanism with a nine-membered transition state (Figure 1.1), wherein phosphate plays two roles: (1) the phosphoric acid hydrogen, as a Brønsted acid, activates the imine and (2) phosphoryl oxygen, as a Brønsted base, activates the nucleophile by coordinating with the hydrogen of phosphite, thereby 21 Chapter promoting Re facial attack to the imine was promoted and the enantioselectivity was increased by proximity effect. As can be seen, the phosphoric acid 80 worked as a bifunctional chiral Brønsted acid bearing both Brønsted acid and Brønsted basic sites. CF3 CF3 O O P O OH CF3 OMe O i-PrO P H + i-PrO R O H m-Xylene 81 selected exmples: O i-PrO P i-PrO HN R i-PrO P i-PrO HN CF3 10 mol% 80 N OMe 82 72 - 97% yield 52 - 90% ee O i-PrO P i-PrO HN Me O i-PrO P i-PrO HN NO2 OMe OMe OMe 82a 84%yield 52% ee 82b 76%yield 69% ee 82c 72%yield 77% ee Cl O O O P P i-PrO i-PrO i-PrO P i-PrO i-PrO i-PrO HN HN HN CF3 OMe OMe 82d 92%yield 84% ee 82e 97%yield 84% ee OMe 82f 86%yield 90% ee Scheme 1.23. Akiyama’s chiral Brønsted acid catalyzed hydrophophonylation of imines. CF3 CF3 O O P O O H O OR P OR Ar H H N CF3Ar F3 C 22 Chapter Figure 1.1. Plausible reaction mechanism of chiral phosphoric acid catalyzed hydrophophonylation of imines. Pettersen and co-workers42 provided a straightforward and novel organocatalytic approach for hydrophosphonylations of imines using commercially available quinine as the catalyst and diethyl phosphonate as the nucleophile. This simple protocol which led to the synthesis of α-amino phosphonates in good yield and with up to 94% ee, made this asymmetric transformation practically important and extended the generality of catalytic enantioselective hydrophosphonylations (Scheme 1.24). H N HO H MeO N 56 10 mol% Quinine O NBoc + P EtO H R EtO H -20 oC, Xylene O EtO P EtO R NHBoc 83 O EtO P EtO O EtO P EtO O EtO P EtO NHBoc 83a 52% yield 88% ee NHBoc 83b 69% yield 92% ee NHBoc 83c 61% yield 94% ee O EtO P EtO Me NHBoc 83d 62% yield 93% ee O EtO P EtO OMe NHBoc 83e 57% yield 94% ee O EtO P EtO Me Cl NHBoc 83a 62% yield 89% ee Scheme 1.24. Pettersen’s hydrophosphonylations of imines using quinine. 23 Chapter References: Quin, L. D., A guide to organophosphorus chemistry. Wiley: New York, 2000; p x, 394 p. (a) Tang, W.; Zhang, X Chem. Rev. 2003, 103, 3029–3069. (b) Crepy, K. V. L.; Imamoto, T., In New Aspects in Phosphorus Chemistry Iii, 2003; Vol. 229, pp 1-40 (c) Crépy, K. V. L.; Imamoto, T., Adv. Synth. Catal. 2003, 345, 79–101. (a) Lu, X.; Zhang, C.; Xu, Z., Acc. Chem. Res 2001, 34, 535–544. (b) Methot, J. L.; Roush, W. R., Adv. Synth. Catal. 2004, 346, 1035–1050. Hiratake, J.; Oda, J., Biosci. Biotech. Biochem. 1997, 61, 211–218. Pietrusiewicz, K. M.; Zablocka, M., Chem. Rev. 1994, 94, 1375–1411. (a) Semenzin, D.; Etemad-Moghadam, G.; Albouy, D.; Diallo, O.; Koenig, M., J. Org. Chem. 1997, 62, 2414–2422. (b) Han, L.-B.; Zhao, C.-Q., J. Org. Chem. 2005, 70, 10121–10123. (a) Shulyupin, M. O.; Kazankova, M. A.; Beletskaya, I. P., Org. Lett. 2002, 4, 761– 763. (b) Han, L.-B.; Tanaka, M., J. Am. Chem. Soc. 1996, 118, 1571–1572. (c) Han, L.-B.; Choi, N.; Tanaka, M., Organometallics, 1996, 15, 3259–3261. (d) Zhao, C.-Q.; Han, L.-B.; Tanaka, M., Organometallics, 2000, 19, 4196–4198. Platonov, A. Y.; Sivakov, A. A.; Chistokletov, V. N.; Maiorova, E. D., Zh. Obshch. Khim. 1999, 69, 514–515. Froestl, W.; Mickel, S. J.; Hall, R. G.; Vonsprecher, G.; Strub, D.; Baumann, P. A.; Brugger, F.; Gentsch, C.; Jaekel, J.; Olpe, H. R.; Rihs, G.; Vassout, A.; Waldmeier, P. C.; Bittiger, H., J. Med. Chem. 1995, 38, 3297–3312. 10 Minami, T.; Okada, Y.; Otaguro, T.; Tawaraya, S.; Furuichi, T.; Okauchi, T., Tetrahedron:Asymmetry 1995, 6, 2469–2474. 11 Simoni, D.; Invidiata, F. P.; Manferdini, M.; Lampronti, I.; Rondanin, R.; Roberti, 24 Chapter M.; Pollini, G. P., Tetrahedron Lett. 1998, 39, 7615–7618. 12 Green, K., Tetrahedron Lett. 1989, 30 (36), 4807–4810. 13 Stockland, R. A.; Taylor, R. I.; Thompson, L. E.; Patel, P. B., Org. Lett. 2005, 7, 851–853. 14 Tanaka, M., In New Aspects in Phosphorus Chemistry Iv, 2004; Vol. 232, pp 25–54. 15 Hanaya, T.; Ohmori, K.; Yamamoto, H.; Armour, M.-A.; Hogg, A. M., Bull. Chem. Soc. Jpn. 1990, 63, 1174–1179. 16 Yamashita, M.; Sugiura, M.; Tamada, Y.; Oshikawa, T.; Clardy, J., Chem. Lett. 1987, 1407–1408. 17 Hanaya, T.; Yamamoto, H.; Yamamoto, H., Bull. Chem. Soc. Jpn. 1992, 65, 1154– 1156. 18 Enders, D.; Tedeschi, L.; Bats, J. W., Angew. Chem. Int. Ed. 2000, 39, 4605–4607. 19 Tedeschi, L.; Enders, D., Org. Lett. 2001, 3, 3515–3517. 20 Haynes, R. K.; Lam, W. W.-L.; Yeung, L.-L., Tetrahedron Lett. 1996, 37, 4729– 4732. 21 Knühl, G.; Sennhenn, P.; Helmchen, G., J. Chem. Soc.,Chem. Commun. 1995, 1845– 1846. 22 Jansen, J. F. G. A.; Feringa, B. L., Tetrahedron:Asymmetry 1990, 1, 719–720. 23 Gourdel, Y.; Pellon, P.; Toupet, L.; LeCorre, M., Tetrahedron Lett. 1994, 35, 1197– 1200. 24 Léautey, M.; Castelot-Deliencourt, G.; Jubault, P.; Pannecoucke, X.; Quirion, J.-C., Tetrahedron Lett. 2002, 43, 9237–9240. 25 Liu, X.; Hu, X. E.; Tian, X.; Mazur, A.; Ebetino, F. H., J. Organomet. Chem. 2002, 646, 212–222. 26 (a) Sadow, A. D.; Haller, I.; Fadini, L.; Togni, A., J. Am. Chem. Soc. 2004, 126, 25 Chapter 14704–14705. (b) Sadow, A. D.; Togni, A., J. Am. Chem. Soc. 2005, 127, 17012– 17024. 27 Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Mazzanti, A.; Sambri, L.; Melchiorre, P., Chem. Commun. 2007, 722–724. 28 Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P., Angew. Chem. Int. Ed. 2007, 46, 4504–4506. 29 Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo, F.; Córdova, A., Angew. Chem. Int. Ed. 2007, 46, 4507–4510. 30 Wang, J.; Heikkinen, L. D.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Wang, W., Adv. Synth. Catal. 2007, 349, 1052–1056. 31 Terada, M.; Ikehara, T.; Ube, H., J. Am. Chem. Soc. 2007, 129, 14112–14113. 32 (a) Merino, P.; Marqués-López, E.; Herrera, R. P., Adv. Synth. Catal. 2008, 350, 1195–1208. (b) Gröger, H.; Hammer, B., Chem. Eur. J. 2000, 6, 943–948. 33 Qian, C.; Huang, T., J. Org. Chem. 1998, 63, 4125–4128. 34 Pudovik, A. N., Konovalova, I. V., Synthesis 1979, 1, 81–96. 35 Yager, K. M.; Taylor, C. M.; Smith, A. B., J. Am. Chem. Soc. 1994, 116, 9377–9378. 36 Lefebvre, I. M.; Evans, S. A., J. Org. Chem. 1997, 62, 7532–7533. 37 Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M., J. Org. Chem. 1995, 60, 6656–6657. 38 Saito, B.; Egami, H.; Katsuki, T., J. Am. Chem. Soc. 2007, 129, 1978–1986. 39 (a) Gröger, H.; Saida, Y.; Arai, S.; Martens, J.; Sasai, H.; Shibasaki, M., Tetrahedron Lett. 1996, 37, 9291–9292. (b) Gröger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M., J. Am. Chem. Soc. 1998, 120, 3089–3103. 40 Joly, G. D.; Jacobsen, E. N., J. Am. Chem. Soc. 2004, 126, 4102–4103. 41 Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K., Org. Lett. 2005, 7, 2583–2585. 42 Pettersen, D.; Marcolini, M.; Bernardi, L.; Fini, F.; Herrera, R. P.; Sgarzani, V.; 26 Chapter Ricci, A., J. Org. Chem. 2006, 71, 6269–6272. 27 [...]... 2CH 73 42e: R1 = Ph(CH 2) 2, R2 = Bn 91 42f: R 1 = Ph(CH2)2 , R 2 = Ph2CH 90 R /S 3 :1 86 :1 5 :1 55 :1 12 :1 54 :1 Scheme 1. 11 Ebetino’s asymmetric Michael addition of phosphinic and aminophosphinic acid An asymmetric Michael addition of phosphinic and aminophosphinic acid have been developed by Ebetino and co-workers25 The phosphinic acids 39a-c were first 11 Chapter 1 treated with TMSCl and transformed... J Org Chem 19 97, 62, 2 414 –2422 (b) Han, L.-B.; Zhao, C.-Q., J Org Chem 2005, 70, 10 1 21 10 123 7 (a) Shulyupin, M O.; Kazankova, M A.; Beletskaya, I P., Org Lett 2002, 4, 7 61 763 (b) Han, L.-B.; Tanaka, M., J Am Chem Soc 19 96, 11 8, 15 71 15 72 (c) Han, L.-B.; Choi, N.; Tanaka, M., Organometallics, 19 96, 15 , 3259–32 61 (d) Zhao, C.-Q.; Han, L.-B.; Tanaka, M., Organometallics, 2000, 19 , 419 6– 419 8 8 Platonov,... Chapter 1 M.; Pollini, G P., Tetrahedron Lett 19 98, 39, 7 615 –7 618 12 Green, K., Tetrahedron Lett 19 89, 30 (36), 4807–4 810 13 Stockland, R A.; Taylor, R I.; Thompson, L E.; Patel, P B., Org Lett 2005, 7, 8 51 853 14 Tanaka, M., In New Aspects in Phosphorus Chemistry Iv, 2004; Vol 232, pp 25–54 15 Hanaya, T.; Ohmori, K.; Yamamoto, H.; Armour, M.-A.; Hogg, A M., Bull Chem Soc Jpn 19 90, 63, 11 74 11 79 16 Yamashita,... Lett 19 87, 14 07 14 08 17 Hanaya, T.; Yamamoto, H.; Yamamoto, H., Bull Chem Soc Jpn 19 92, 65, 11 54– 11 56 18 Enders, D.; Tedeschi, L.; Bats, J W., Angew Chem Int Ed 2000, 39, 4605–4607 19 Tedeschi, L.; Enders, D., Org Lett 20 01, 3, 3 515 –3 517 20 Haynes, R K.; Lam, W W.-L.; Yeung, L.-L., Tetrahedron Lett 19 96, 37, 4729– 4732 21 Knühl, G.; Sennhenn, P.; Helmchen, G., J Chem Soc.,Chem Commun 19 95, 18 45– 18 46... New Aspects in Phosphorus Chemistry Iii, 2003; Vol 229, pp 1- 40 (c) Crépy, K V L.; Imamoto, T., Adv Synth Catal 2003, 345, 79 10 1 3 (a) Lu, X.; Zhang, C.; Xu, Z., Acc Chem Res 20 01, 34, 535–544 (b) Methot, J L.; Roush, W R., Adv Synth Catal 2004, 346, 10 35 10 50 4 Hiratake, J.; Oda, J., Biosci Biotech Biochem 19 97, 61, 211 – 218 5 Pietrusiewicz, K M.; Zablocka, M., Chem Rev 19 94, 94, 13 75 14 11 6 (a) Semenzin,... 4507–4 510 30 Wang, J.; Heikkinen, L D.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Wang, W., Adv Synth Catal 2007, 349, 10 52 10 56 31 Terada, M.; Ikehara, T.; Ube, H., J Am Chem Soc 2007, 12 9, 14 112 14 113 32 (a) Merino, P.; Marqués-López, E.; Herrera, R P., Adv Synth Catal 2008, 350, 11 95 12 08 (b) Gröger, H.; Hammer, B., Chem Eur J 2000, 6, 943–948 33 Qian, C.; Huang, T., J Org Chem 19 98, 63, 412 5– 412 8 34... N R1 R2 O + MeO H P OMe H HN (R) - LPB 67 THF, - 15 o C, 24h R1 R 1 = alkyl R2 OMe P OMe O 68 yield 27 - 87% ee 49 - 96% OMe (R) - LPB 67 = 68a 10 mol% (R) - LPB 67 70% yield, 96% ee K O O La O K NH O K R1 MeO O OMe P OMe O Ph O Ph NH R1 OMe 68b 5 mol% (R) - LPB 67 82% yield, 92% ee P OMe O Scheme 1. 19 Lanthanum-potassium-BINOL complex catalyzed hydrophosphination of imines The first catalytic enantioselective. .. P Pr P Pr CN 46a : 8h 71% yield 70% ee 46b : 24h 10 %yield 32% ee 46c: 24h 70% ee Cy P R2 P CN t t Bu CN Ph Bu P CN i Ad CN Ad P CN 46d : 8h 87%yield 89% ee 46e :96h, 95%yield 94% ee Scheme 1. 12 Organonickel complex catalyzed enantioselective phospha-Michael addition of secondary phosphines 1. 1.3 Organocatalyst catalyzed asymmetric phospha-Michael reactions Recently, Melchiorre and co-workers 27 reported... 45% ee NO2 57f: 62% yield, 60% ee Scheme 1. 15 Quinine catalyzed enantioselective conjugate addition of diphenyl phosphonate to nitroolefins Terada and co-workers 31 demonstrated the highly enantioselective 1, 4-addition reaction of nitroalkenes with diphenyl phosphonate catalyzed by an axially chiral guanidine 58 In order to obtain good results (85 – 97% ee), the reactions were conducted under low reaction... 412 5– 412 8 34 Pudovik, A N., Konovalova, I V., Synthesis 19 79, 1, 81 96 35 Yager, K M.; Taylor, C M.; Smith, A B., J Am Chem Soc 19 94, 11 6, 9377–9378 36 Lefebvre, I M.; Evans, S A., J Org Chem 19 97, 62, 7532–7533 37 Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M., J Org Chem 19 95, 60, 6656–6657 38 Saito, B.; Egami, H.; Katsuki, T., J Am Chem Soc 2007, 12 9, 19 78 19 86 39 (a) Gröger, H.; Saida, Y.; Arai, S.; Martens, . 14 1. 1 Asymmetric phospha-Michael reactions 1. 1 .1 Asymmetric phospha-Michael reactions through chiral starting materials and chiral auxiliaries Asymmetric versions of phospha-Michael reactions. O O Me Me O P O O H Ph Ph Ph Ph a,b 98% O O Me Me OH OH Ph Ph Ph Ph 10 9 NO 2 R NO 2 P R O HO HO 8 6-9 1 % c O O Me Me O P O O Ph Ph Ph Ph R NO 2 d, e 6 5-9 4 % R=Ph,pBip h, 3,4, 5- (MeO) 3 Ph, pMePh, 2-Naphthyl 12 , de = 8 4-9 6% 11 ee =8 1- 9 5% Scheme 1. 4. Enders’s asymmetric phospha-Michael. 55 :1 42e :R 1 =Ph(CH 2 ) 2 ,R 2 =Bn 91 12 :1 42f:R 1 =Ph(CH 2 ) 2 ,R 2 =Ph 2 CH 90 54 :1 O N O O R 2 P TMS O R 1 TMSO H + Transition State model: 43a-f 40 0 o Ctor.t.,24h EtOH, -1 0 o C, 30min Scheme 1. 11.